Pamoate salt of monoamine anti-parkinson&#39;s agents, method of preparation and use thereof

ABSTRACT

In various embodiments, provided herein are pamoate salts of monoamine Anti-Parkinsons disease agents including rotigotine, ropinirole, pramipexole, selegiline, rasagiline, and safinamide, pharmaceutical composition comprising the same, methods of preparing the same, and methods of using the same. For example, the pamoate salt herein can be characterized by a molar ratio of rotigotine, ropinirole, pramipexole, selegiline, rasagiline, or safinamide to pamoic acid of about 1:1 or about 2:1. The pamoate salt herein can also be crystalline including anhydrous, hydrate or solvate forms, or their polymorphs, or amorphous. The pamoate salts described herein can provide a long acting and/or extended release profile of the monoamine agents tor the treatment of Parkinsons disease (PD). Thus, also provided herein are methods of preparing a long acting and/or extended release injectable formulation of the monoamine agents using their respective pamoate salts. And in some embodiments, provided herein are methods of treating a subject in need thereof comprising administering a pharmaceutical composition comprising a pamoate salt of rotigotine, ropinirole, pramipexole, selegiline, rasagiline, and/or safinamide.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/639,170, filed Feb. 14, 2020, now U.S. Pat. No. 11,234,961, issuedFeb. 1, 2022, which is the U.S. National Phase of InternationalApplication No. PCT/US2018/046916, filed Aug. 17, 2018, which claimsbenefit of U.S. Provisional Application No. 62/546,984, filed on Aug.17, 2017, the content of each of which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

In various embodiments, the present invention generally relates topamoate salts of anti-Parkinson's disease agents, for example, pamoatesalts of rotigotine, ropinirole, pramipexole, selegiline, rasagiline,and/or safinamide, pharmaceutical compositions comprising such salts,methods of preparing such salts, and methods of treating a subject inneed thereof with such salts and compositions.

BACKGROUND

Parkinson's disease (PD) is a motor system disorder of the nervoussystem. It is characterized as a progressive disorder that affectsmovement and results in the loss of dopamine-producing brain cells,causing tremor in the hands, arms, legs, jaw, and face and/or rigidityor stiffness of the limbs and trunk. The primary symptoms includemuscular rigidity, slowness of movement, a resting tremor, and posturalinstability.

The most common anti-Parkinson's disease drugs are to either replace thedopamine levels in the brain, mimic the actions of dopamine orslow/inhibit the degradation of dopamine in the brain. The maincategories of dopaminergic drugs include dopamine agonists such asrotigotine, ropinirole, and pramipexole, of which the chemicalstructures are depicted below. Drugs from the category of monoamineoxidase-B (MAO-B) inhibitors such as selegiline, rasagiline, andsafinamide (see chemical structures below) increase the level ofdopamine in the basal ganglia by blocking its metabolism. These drugsinhibit MAO-B which breaks down dopamine secreted by the dopaminergicneurons. The reduction in MAO-B activity results in increased L-DOPA inthe nervous system thus alleviating the symptom from PD.

Currently available treatment of PD from the dopamine agonists and MAO-Binhibitors typically provide for daily oral administration. However,there is a need for a better dosing regimen of anti-PD drugs which can,for example, increase patient compliance and/or reduce side effects.

SUMMARY

00061 In various embodiments, the present invention provides a varietyof solid state forms, such as pamoate salts of anti-Parkinson's diseaseagents, e.g., monoamine anti-Parkinson's disease agents (hereinafter“monoamine agent(s)”), in different novel polymorphic forms, and moreparticularly, pamoate salts of rotigotine, pamoate salts of ropinirole,pamoate salts of pramipexole, pamoate salts of selegiline, pamoate saltsof rasagiline, and/or pamoate salts of safinamide. In some embodiments,the present invention also provides pharmaceutical compositionscomprising one or more of such salts, methods of preparing such salts,and methods of treating a subject or patient (such as a human) in needthereof with one or more of such salts and pharmaceutical compositions.In some embodiments, the present invention also provides formulationscomprising one or more of the pamoate salts of the monoamine agents witha long acting and/or extended release profile. In any of the embodimentsdescribed herein, the monoamine agent can be rotigotine, ropinirole,pramipexole, selegiline, rasagiline, and/or safinamide. In any of theembodiments described herein, the monoamine agent can also beropinirole, pramipexole, or rotigotine.

In some embodiments, the present invention provides novel pamoate salts,e.g., in different polymorphic forms, of monoamine agents. In someembodiments, the molar ratio of the monoamine agent's free base topamoic acid is about 1:1 (which is referred to herein as themono-pamoate salt of the monoamine agent). In some embodiments, themolar ratio of the monoamine agent's free base to pamoic acid is about2:1 (which is herein referred as the semi-pamoate salt of the monoamineagent). In some embodiments, the pamoate salt of the monoamine agent is(1) crystalline, including anhydrous, hydrate, solvate forms and theirpolymorphs, or (2) amorphous. In some embodiments, the above salts canbe especially useful in preparing a formulation, such as an extendedrelease formulation (or composition) in which the release rate isminimally dependent on the pH of the environment at the injection site.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a pamoate salt of a monoamine agent and at leastone pharmaceutically acceptable carrier. In some embodiments, thecarrier is a viscous aqueous or nonaqueous carrier.

In some embodiments, the present invention provides a method ofpreparing a pamoate salt of a monoamine agent comprising treating ormixing the monoamine agent with pamoic acid or treating or mixing a saltof the monoamine agent with a pamoate salt in a solvent.

In some embodiments, the present invention provides a method of treatinga subject having syndrome associated with Parkinson's disease comprisingadministering a therapeutically effective amount of a pamoate salt of amonoamine agent or a pharmaceutical composition comprising a pamoatesalt of a monoamine agent and at least one pharmaceutically acceptablecarrier to a subject in need of treatment thereof. In some embodiments,the composition is administered by injection. In some particularembodiments, the composition is administered intramuscularly orsubcutaneously.

In some embodiments, the present invention provides a formulation (orcomposition) comprising a pamoate salt of a monoamine agent as an activeingredient or active agent, and one or more pharmaceutically acceptablecarriers. In some embodiments, the formulation (or composition) can meetthe unmet need for a stable, pharmaceutically suitable formulation witha controlled and/or sustained release rate which can be useful as adepot formulation or for intramuscular or subcutaneous use.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. It is tobe understood that both the foregoing summary and the following detaileddescription are exemplary and explanatory only, and are not restrictiveof the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention.

FIG. 1 depicts an X-ray powder diffraction (“XRPD”) spectrum ofropinirole pamoate Form A (1:1 molar ratio of ropinirole to pamoic acid)obtained from a mixture of DMSO and water.

FIG. 2 depicts a differential scanning calorimetry (“DSC”) thermogram ofropinirole pamoate Form A (1:1 molar ratio of ropinirole to pamoic acid)obtained from a mixture DMSO and water.

FIG. 3 depicts an XRPD spectrum of ropinirole pamoate Form B (1:1 molarratio of ropinirole to pamoic acid) obtained from heating materialsdepicted in FIGS. 1 and 2 at 170° C. for 30 minutes.

FIG. 4 depicts a DSC thermogram of ropinirole pamoate Form B (1:1 molarratio of ropinirole to pamoic acid) obtained from heating materialsdepicted in FIGS. 1 and 2 at 170° C. for 30 minutes.

FIG. 5 depicts an XRPD spectrum of ropinirole pamoate Form C (2:1 molarratio of ropinirole to pamoic acid) obtained from a mixture of ethanol,water and PEG6000.

FIG. 6 depicts a DSC thermogram of ropinirole pamoate Form C (2:1 molarratio of ropinirole to pamoic acid) obtained from a mixture of ethanol,water and PEG6000.

FIG. 7 depicts an XRPD spectrum of ropinirole pamoate Form D (1:1 molarratio of ropinirole to pamoic acid) obtained from a mixture of DMSO andacetonitrile.

FIG. 8 depicts a DSC thermogram of ropinirole pamoate Form D (1:1 molarratio of ropinirole to pamoic acid) obtained from a mixture of DMSO andacetonitrile.

FIG. 9 depicts an XRPD spectrum of ropinirole pamoate Form E (2:1 molarratio of ropinirole to pamoic acid) obtained from a mixture of ethanol,water and poly(allylamine hydrochloride).

FIG. 10 depicts a DSC thermogram of ropinirole pamoate Form E (2:1 molarratio of ropinirole to pamoic acid) obtained from a mixture of ethanol,water and poly(allylamine hydrochloride).

FIG. 11 depicts an XRPD spectrum of rotigotine pamoate Form I (1:1 molarratio of rotigotine to pamoic acid) obtained from a mixture of ethanol,acetone, and n-heptane.

FIG. 12 depicts a DSC thermogram of rotigotine pamoate Form I (1:1 molarratio of rotigotine to pamoic acid) obtained from a mixture of ethanol,acetone, and n-heptane.

FIG. 13 depicts an XRPD spectrum of pramipexole pamoate Form 1 (1:1molar ratio of pramipexole to pamoic acid) obtained from a mixture ofacetone and water.

FIG. 14 depicts a DSC thermogram of pramipexole pamoate Form 1 (1:1molar ratio of pramipexole to pamoic acid) obtained from a mixture ofacetone and water.

FIG. 15 depicts an XRPD spectrum of pramipexole pamoate Form 2 (1:1molar ratio of pramipexole to pamoic acid) obtained from a mixture ofacetone and methanol.

FIG. 16 depicts a DSC thermogram of pramipexole pamoate Form 2 (1:1molar ratio of pramipexole to pamoic acid) obtained from a mixture ofacetone and methanol.

FIG. 17 depicts an XRPD spectrum of pramipexole pamoate Form 3 (2:1molar ratio of pramipexole to pamoic acid) obtained from a solution ofethyl acetate.

FIG. 18 depicts a DSC thermogram of pramipexole pamoate Form 3 (2:1molar ratio of pramipexole to pamoic acid) obtained from a solution ofethyl acetate.

FIG. 19 depicts an XRPD spectrum of pramipexole pamoate Form 4 (2:1molar ratio of pramipexole to pamoic acid) obtained from a solution oftetrahydrofuran.

FIG. 20 depicts a DSC thermogram of pramipexole pamoate Form 4 (2:1molar ratio of pramipexole to pamoic acid) obtained from a solution oftetrahydrofuran.

FIG. 21 depicts a ¹H-NMIR spectrum of pramipexole pamoate (1:1 molarratio of pramipexole to pamoic acid) obtained from a mixture of acetoneand water.

FIG. 22 depicts a ¹H-NMIR spectrum of pramipexole pamoate (2:1 molarratio of pramipexole to pamoic acid) obtained from a solution oftetrahydrofuran.

FIG. 23 depicts a ¹H-NMIR spectrum of Ropinirole pamoate (1:1 molarratio of Ropinirole to pamoic acid) obtained from Example 1.

FIG. 24 depicts a ¹H-NMIR spectrum of Ropinirole pamoate (2:1 molarratio of Ropinirole to pamoic acid) obtained from Example 3.

FIG. 25 depicts a ¹H-NMR spectrum of Rotigotine pamoate (1:1 molar ratioof Rotigotine to Pamoic acid) obtained from Example 6.

FIG. 26 depicts a ¹H-NMIR spectrum of pramipexole pamoate (2:1 molarratio of pramipexole to pamoic acid) obtained from Example 9.

DETAILED DESCRIPTION OF THE INVENTION

Prior to describing the details of the various embodiments of theinvention, it is to be understood that the present invention is notlimited in its application to the details of construction and thearrangement of components set forth in the following descriptions. Theinvention is capable of other embodiments and of being practiced or ofbeing carried out in various ways by the ones skilled in the art.

It is also specifically understood that any numerical value recitedherein includes all values from the lower value to the upper value,i.e., all possible combinations of numerical values between the lowestvalue and the highest value enumerated are to be considered to beexpressly stated in the present application.

Currently available treatment of PD from the dopamine agonists and MAO-Binhibitors typically provide for daily oral administration. For example,pramipexole, a widely used dopamine agonist for the last decade as bothmonotherapy for patients with early Parkinson's disease as well as forpatients with more advanced disease, is administered either three timesa day or once daily. Unfortunately, development of motor and non-motorcomplications during the course of Parkinson's disease represents amajor challenge for the current therapeutic management (M. Senek, D.Nyhohn, CNS Drugs. 28(1):19-27, 28314). At advanced disease stages,patients frequently experience PD symptoms-such as bradykinesia- anddyskinesias, in response to fluctuations in drug concentrations. Studiesindicated that continuous infusion of the dopamine agonist or intestinalinfusion of levodopa reduce such fluctuations in both pharmacokineticsand motor function. These studies suggested that the continuous deliveryof anti-PD drugs such as dopamine agonists would provide significantbenefits alleviating the motor and non-motor complications. To theseobjectives, the effort has been made to develop continuous deliveryformulation such as transdermal delivery of rotigotine and continuoussubcutaneous infusion of apomorphine to provide more continuous drugconcentrations, sustained benefits and minimized side effects. However,these regimens are far less optimal only providing daily short durationof continuous drug concentrations. Furthermore, long releasing regimenof more than 24 hours would also help patients with compliance as thepatients with advanced PD are often non-compliant, making it difficultto assess whether or not a patient has received the proper dosage ofmedication. Taken together, there is still a significant benefit andunmet medical need to develop continuous drug delivery formulation oflonger than 24 hours (e.g. extended release for 7 days) to betteralleviate motor and non-motor complications for the PD patients.

Monoamine anti-PD agents are weak organic bases. In an alkaline solution(high pH), they exist as the free base form. Aqueous solubility of themonoamine agents increase with decreasing pH of the solution due to anincreasing fraction of the drug being ionized. At high concentrations ofthe ionized drug (protonated amine), the salt form will precipitate outdue to exceeding solubility product (K_(sp)). The nature of the drug andcounter-ion determine the K_(sp) and the associated solid stateproperties of the salt.

There are a wide range of counter-ions to prepare salts of bases usinginorganic and organic acids. The most frequently used anions to form asalt of a basic drug is the hydrochloride form. For example, Requip XL,an extended-release tablet and a commercial product of dopamine agonistropinirole for oral administration, is a hydrochloride salt. Transdermalpatch of ropinirole also use its hydrochloride salt as activepharmaceutical ingredient (API) (U.S. Pat. No. 5,807,570 by Chen etal.). In the extended release tablet formulation, pramipexoledihydrochloride monohydrate was dispersed in a matrix comprising ahydrophilic polymer to achieve 24 hours release (US patent Nos. 7695734by Friedl et al. and 8399016 by Amidon et al.). Using benzene sulfonicacid salts of pramipexole has also been described in U.S. Pat. No.7,365,086 by Eupen et al. as alternative pharmaceutical active agents.The administration of rotigotine hydrochloride in depot form has beendescribed in the U.S. Pat. No. 8,604,076 by Rimpler et al. The depotregimen was intended to provide therapeutically significant plasmalevels of rotigotine over a period of at least 24 hours afteradministration to a patient. These salts of the monoamine agents wereprepared to improve physical properties including stability, solubilityor increased dissolution rate for administration. The selection of therespective salts rendered them desirable properties for immediate orextended release dosage form. However, these formulations, even withextended release format, are administered for no longer than 24 hours.As a result, one objective is to provide improved methods of deliveringthe monoamine agents significantly less frequently than the current24-hour dosing interval and formulations can be manufactured in a costeffective manner.

The present inventor has discovered that it is desirable to formulatethe monoamine agents, e.g., in a depot formulation or as an injectableformulation such as an intramuscular or subcutaneous formulation, toassure consistent and proper dosage of the drug substance and tomaximize the clinical benefits through maintaining a sustained andcontinuous drug concentration and improve patient compliance.

It is known that the pH of muscle tissue can fluctuate with exercise,stress, and injury which may impact drug solubility, and thus the rateof absorption of injectable drugs. Therefore, in some embodiments, it isalso desirable to develop an injectable extended release formulation inwhich the release rate of the active ingredient is minimally dependenton pH fluctuation, such as those related to exercise, stress, and/orinjury.

In some embodiments, the present inventor has found that a solid stateor solid forms of anti-Parkinson's disease agents such as a monoamineanti-Parkinson's disease (anti-PD) agent pamoate salt, can beadvantageous. Among other advantages, pamoate salts of the monoamineagents with specific polymorphic form and particle size distribution ina suitable formulation can provide a desired long acting and/or extendedrelease profile. Such pamoate salts of the monoamine agent can providean alternative and more desirable dosing regimen for treatment ofpatients suffering from Parkinson's disease (PD). It will also havesuperior drug absorption and distribution profiles compared to theexisting oral drug products by providing a continuous delivery of drug,which would maintain stable plasma drug levels and reduce maximum tominimum plasma drug concentration ratio during dosing intervals, thus,ultimately improve safety profile and enhance clinical effectiveness.

The chemical structure of pamoic acid is:

The molecular weight of pamoic acid is 388 g/mol, the pK_(a1) is 2.51,and pK_(a2) is 3.1. With respect to the chemical structure of pamoicacid, both carboxylic counter ions can form salt with the amine of themonoamine agents, resulting in a molar ratio of the monoamine agents topamoic acid of about 1:1 or about 2:1, such as those specified in FIGS.1-20.

In one embodiment, the invention provides pamoate salts of anti-PDagents such as monoamine anti-PD agents and compositions andformulations containing said pamoate salts. Preferably, the pamoate saltis characterized by a molar ratio of the monoamine agent to pamoic acidof about 1:1 or about 2:1. The pamoate salt can be crystalline,anhydrous, hydrated, solvated, or amorphous.

In another embodiment, the invention provides pamoate salt ofropinirole, e.g., five crystalline Forms, Form A to Form E, of pamoatesalt of ropinirole. Forms A, B, and D of pamoate salt of ropinirole eachhas a molar ratio of ropinirole to pamoic acid of about 1:1, whereasForms C and E of pamoate salt of ropinirole each has a molar ratio ofropinirole to pamoic acid of about 2:1. Pamoate salts of ropinirole canbe prepared by those skilled in the art in view of the presentdisclosure, see e.g., the Examples section. For example, Forms A, B, C,D, E of pamoate salt of ropinirole can be prepared by following theprocedures described in Examples 1-5 in the Examples section,respectively.

In some embodiments, the crystalline Form A to Form E of pamoate salt ofropinirole can be characterized by one or more of the followingproperties: (1) an X-ray powder diffraction pattern having peak(s)expressed as 2-theta from 3 to 40 degrees substantially in accordancewith (e.g., within ±0.2° 2-theta) one or more (e.g., two or more, threeor more, etc., e.g., 1, 2, 3, 4, 5, 6, or more) of the main peaks shownin FIGS. 1, 3, 5, 7, 9, respectively, for each crystalline form; (2) anX-ray powder diffraction pattern substantially in accordance with thoseshown in FIGS. 1, 3, 5, 7, 9, respectively, for each crystalline form;(3) a differential scanning calorimetry thermogram pattern substantiallyin accordance with those shown in FIGS. 2, 4, 6, 8, 10, respectively,for each crystalline form; and (4) any combinations of (1), (2) and (3),respectively for each crystalline form. As used herein, “main peaks”refer to peaks in an MOD spectrum (e.g., as shown in the FIGs and Tablesherein) that have a relative intensity (height) of about 15% or more,preferably, about 30% or more (e.g., 35% or more, 50% or more, 60% ormore, 70% or more, 80% or more, or 90% or more). In some embodiments,“main peaks” refers to peaks in an XRPD spectrum (e.g., as shown in theFIGs and Tables herein) that have a relative intensity (height) of about80% or more.

For example, in some embodiments, ropinirole pamoate in crystalline FormA can be characterized by an XRPD spectrum having one or more (e.g., 4or more, 6 or more, 8 or more, 10 or more, 12 or more, or all of) of thefollowing peaks: 4.3, 9.8, 11.5, 14.4, 16.0, 17.1, 18.6, 19.1, 20.5,21.0, 23.1, 23.8, 26.5, and 26.9, ±0.2° 2-theta. In some embodiments,ropinirole pamoate in crystalline Form A can be characterized by an XRPDspectrum having one or more (e.g., 2 or more, 4 or more, 6 or more, orall of) of the following peaks: 4.3, 9.8, 17.1, 18.6, 19.1, 20.5, 21.0,and 23.1, ±0.2° 2-theta. In some embodiments, ropinirole pamoate incrystalline Form A can be characterized by an XRPD spectrum having oneor more (e.g., 1, 2, 3, or 4) of the following peaks: 4.3, 17.1, 18.6,and 20.5, ±0.2° 2-theta.

In some embodiments, ropinirole pamoate in crystalline Form B can becharacterized by an XRPD spectrum having one or more (e.g., 4 or more, 6or more, 8 or more, 10 or more, or all of) of the following peaks: 9.4,11.5, 12.0, 12.7, 15.6, 16.4, 17.2, 18.7, 21.0, 23.1, 23.4, and 26.2,±0.2° 2-theta. In some embodiments, ropinirole pamoate in crystallineForm B can be characterized by an XRPD spectrum having one or more(e.g., 2 or more, 4 or more, 6 or more, or all of) of the followingpeaks: 11.5, 12.0, 12.7, 16.4, 21.0, 23.1, 23.4, and 26.2, ±0.2°2-theta. In some embodiments, ropinirole pamoate in crystalline Form Bcan be characterized by an XRPD spectrum having one or more (e.g., 2 ormore, 4 or more, or all of) of the following peaks: 11.5, 16.4, 21.0,23.1, 23.4, and 26.2, ±0.2° 2-theta.

In some embodiments, ropinirole pamoate in crystalline Form C can becharacterized by an XRPD spectrum having one or more (e.g., 1, 2, 3, or4) of the following peaks: 8.0, 9.5, 16.1, and 18.8, ±0.2° 2-theta. Insome embodiments, ropinirole pamoate in crystalline Form C can becharacterized by an XRPD spectrum having peaks at 16.1 and 18.8, ±0.2°2-theta.

In some embodiments, ropinirole pamoate in crystalline Form D can becharacterized by an XRPD spectrum having one or more (e.g., 1, 2, 3, 4,5, or 6) of the following peaks: 14.3, 17.9, 21.5, 22.4, 24.8, and 25.2,±0.2° 2-theta. In some embodiments, ropinirole pamoate in crystallineForm D can be characterized by an XRPD spectrum having one or more (1,2, or 3) of the following peaks: 14.3, 17.9, and 25.2, ±0.2° 2-theta,for example, ropinirole pamoate in crystalline Form D can becharacterized by an XRPD spectrum having a peak at 17.9±0.2° 2-theta.

In some embodiments, ropinirole pamoate in crystalline Form E can becharacterized by an XRPD spectrum having one or more (e.g., 4 or more, 6or more, 8 or more, 10 or more, or all of) of the following peaks: 11.1,11.7, 12.0, 15.5, 18.8, 19.6, 20.2, 21.0, 22.9, 23.6, 26.1, and 26.6,±0.2° 2-theta. In some embodiments, ropinirole pamoate in crystallineForm E can be characterized by an XRPD spectrum having one or more(e.g., 2 or more, 4 or more, or all of) of the following peaks: 11.1,11.7, 12.0, 21.0, 26.1, and 26.6, ±0.2° 2-theta. In some embodiments,ropinirole pamoate in crystalline Form E can be characterized by an XRPDspectrum having one or more (e.g., 1, 2, or 3) of the following peaks:11.7, 12.0, and 21.0, ±0.2° 2-theta.

In some embodiments, each of the crystalline Form A to Form E of pamoatesalts of ropinirole can be substantially pure, for example, each formcan be substantially free of other crystalline or amorphous forms ofpamoate salts of ropinirole (e.g., less than 20%, less than 10%, lessthan 5%, or not detectable with the XRPD method described herein).However, in some embodiments, each of the crystalline Form A to Form Eof pamoate salts of ropinirole can exist in a mixture with one or moreother forms of pamoate salts of ropinirole, crystalline or amorphous.

In yet another embodiment, the invention relates to pamoate salt ofrotigotine, e.g., crystalline Form I of pamoate salt of rotigotine,which has a molar ratio of rotigotine to pamoic acid of about 1:1.Pamoate salts of rotigotine can be prepared by those skilled in the artin view of the present disclosure, see e.g., the Examples section. Forexample, Form I of pamoate salt of rotigotine can be prepared byfollowing the procedures described in Example 6 in the Examples section.

In some embodiments, the crystalline Form I of pamoate salt ofrotigotine can be characterized by one or more of the followingproperties: (1) an X-ray powder diffraction pattern having peak(s)expressed as 2-theta from 3 to 40 degrees substantially in accordance(e.g., within ±0.2° 2-theta) one or more (e.g., two or more, three ormore, etc., e.g., 1, 2, 3, 4, 5, 6, or more) of with the main peaksshown in FIG. 11; (2) an X-ray powder diffraction pattern substantiallyin accordance with that shown in FIG. 11; (3) a differential scanningcalorimetry thermogram pattern substantially in accordance with thatshown in FIGS. 12; and (4) any combinations of (1), (2) and (3). Forexample, in some embodiments, Form I of pamoate salt of rotigotine canbe characterized by an XRPD spectrum having one or more (e.g., 1, 2, 3,4, 5, 6, 7, or 8) of the following peaks: 4.6, 9.3, 17.5, 18.7, 24.2,26.4, 28.2, and 29.6, ±0.2° 2-theta. In some embodiments, Form I ofpamoate salt of rotigotine can be characterized by an XRPD spectrumhaving one or both peaks at 4.6 and 9.3, ±0.2° 2-theta. In someembodiments, the crystalline Form I of pamoate salt of rotigotine can besubstantially pure, for example, substantially free of other crystallineor amorphous forms of pamoate salt of rotigotine (e.g., less than 20%,less than 10%, less than 5%, or not detectable with the XRPD methoddescribed herein). However, in some embodiments, the crystalline Form Iof pamoate salt of rotigotine can exist in a mixture with one or moreother forms of pamoate salt of rotigotine, crystalline or amorphous.

In yet another embodiment, the invention relates to pamoate salt ofpramipexole, e.g., crystalline forms, Form 1 to Form 4, of pamoate saltof pramipexole. Pamoate salts of pramipexole can be prepared by thoseskilled in the art in view of the present disclosure, see e.g., theExamples section. For example, Forms 1-4 of pamoate salt of pramipexolecan be prepared by following the procedures described in Examples 7-10in the Examples section, respectively.

Forms 1 and 2 of pamoate salt of pramipexole each has a molar ratio ofpramipexole to pamoic acid of about 1:1, whereas Forms 3 and 4 ofpamoate salt of pramipexole each has a molar ratio of pramipexole topamoic acid of about 2:1. In some embodiments, the crystalline Form 1 toForm 4 of pamoate salt of pramipexole can be characterized by one ormore of the following properties: (1) an X-ray powder diffractionpattern having peak(s) expressed as 2-theta from 3 to 40 degreessubstantially in accordance with (e.g., within ±0.2° 2-theta) one ormore (e.g., two or more, three or more, etc., e.g., 1, 2, 3, 4, 5, 6, ormore) of the main peaks shown in FIG. 13, 15, 17, 19, respectively, foreach crystalline form; (2) an X-ray powder diffraction patternsubstantially in accordance with those shown in FIG. 13, 15, 17, 19,respectively, for each crystalline form; (3) a differential scanningcalorimetry thermogram pattern substantially in accordance with thoseshown in FIG. 14, 16, 18, 20, respectively for each crystalline form;and (4) any combinations of (1), (2) and (3).

In some embodiments, Form 1 of pamoate salt of pramipexole can becharacterized by an XRPD spectrum having one or more (e.g., 1, 2, 3, 4,5, 6, 7, 8, or 9) of the following peaks: 7.7, 11.8, 13.8, 15.3, 18.9,21.1, 23.1, 23.7, and 26.4, ±0.2° 2-theta. In some embodiments, Form 1of pamoate salt of pramipexole can be characterized by an XRPD spectrumhaving one or more (e.g., 1, 2, or 3) of the following peaks: 13.8,15.3, and 21.1, ±0.2° 2-theta.

In some embodiments, Form 2 of pamoate salt of pramipexole can becharacterized by an XRPD spectrum having one or more (e.g., 1, 2, 3, 4,5, 6, 7, or 8) of the following peaks: 12.0, 15.0, 17.2, 20.4, 20.9,22.5, 23.3, and 25.4, ±0.2° 2-theta. In some embodiments, Form 2 ofpamoate salt of pramipexole can be characterized by an XRPD spectrumhaving one or more (e.g., 1, 2, 3, 4, 5, or 6) of the following peaks:12.0, 15.0, 20.4, 20.9, 22.5, and 23.3, ±0.2° 2-theta. In someembodiments, Form 2 of pamoate salt of pramipexole can be characterizedby an XRPD spectrum having one or more (e.g., 1, 2, 3, or 4) of thefollowing peaks: 12.0, 15.0, 20.4, and 20.9, ±0.2° 2-theta.

In some embodiments, Form 3 of pamoate salt of pramipexole can becharacterized by an XRPD spectrum having one or more (e.g., 1, 2, 3, 4,5, 6, 7, or 8) of the following peaks: 10.7, 12.7, 13.5, 14.9, 16.3,18.1, 18.7, and 22.3, ±0.2° 2-theta. In some embodiments, Form 3 ofpamoate salt of pramipexole can be characterized by an XRPD spectrumhaving one or more (e.g., 1, 2, 3, 4, 5, or 6) of the following peaks:10.7, 12.7, 13.5, 14.9, 18.7, and 22.3, ±0.2° 2-theta. In someembodiments, Form 3 of pamoate salt of pramipexole can be characterizedby an XRPD spectrum having one or more (e.g., 1, 2, 3, or 4) of thefollowing peaks: 10.7, 12.7, 13.5, and 14.9, ±0.2° 2-theta.

In some embodiments, Form 4 of pamoate salt of pramipexole can becharacterized by an XRPD spectrum having one or more (e.g., 1, 2, 3, 4,5, 6, 7, 8, 9, or 10) of the following peaks: 6.1, 13.5, 14.9, 17.9,18.9, 21.3, 21.8, 22.4, 23.2, and 24.0, ±0.2° 2-theta. In someembodiments, Form 4 of pamoate salt of pramipexole can be characterizedby an XRPD spectrum having one or more (e.g., 1, 2, 3, 4, 5, or 6) ofthe following peaks: 6.1, 17.9, 18.9, 21.3, 23.2, and 24.0, ±0.2°2-theta. In some embodiments, Form 4 of pamoate salt of pramipexole canbe characterized by an XRPD spectrum having one or more (e.g., 1, 2, 3,or 4) of the following peaks: 6.1, 17.9, 21.3, and 23.2, ±0.2° 2-theta.In some embodiments, Form 4 of pamoate salt of pramipexole can becharacterized by an XRPD spectrum having the following peaks: 6.1 and17.9, ±0.2° 2-theta.

In some embodiments, each of the crystalline Form 1 to Form 4 of pamoatesalt of pramipexole can be substantially pure, for example, each formcan be substantially free of other crystalline or amorphous forms ofpamoate salt of pramipexole (e.g., less than 20%, less than 10%, lessthan 5%, or not detectable with the XRPD method described herein).However, in some embodiments, each of the crystalline Form 1 to Form 4of pamoate salt of pramipexole can exist in a mixture with one or moreother forms of pamoate salt of pramipexole, crystalline or amorphous.

In some embodiments, the invention further provides a pharmaceuticalcomposition comprising one or more of the pamoate salts of the monoamineanti-PD agents (e.g., any of those described herein, e.g., Forms A-E ofpamoate salt of ropinirole, Form I of pamoate salt of rotigotine, Forms1-4 of pamoate salt of pramipexole) and at least one pharmaceuticallyacceptable carrier. In some embodiments, the pharmaceutical compositionis an intramuscularly or subcutaneously injectable formulation. In onepreferred embodiment, the pharmaceutical composition is an extendedrelease formulation comprising pamoate salts of the monoamine agents anda polymer (e.g., a release control polymer). Polymers suitable for usein the extended release formulations include any of those known in theart. Some of which can be found, for example, in Remington'sPharmaceutical Sciences, latest edition, Mack Publishing Co. In someembodiments, the extended release can be based on the slow dissolutionrate of the pamoate salts herein. In some embodiments, the extendedrelease formulation can also be free or substantially free of a polymer,for example, the extended release formulation can be free orsubstantially free a release control polymer.

In another embodiment, the pharmaceutically acceptable carrier is aviscous aqueous or nonaqueous fluid. In some embodiments, the viscousaqueous or nonaqueous fluid can have a viscosity of at least 20 cp at20° C. In some embodiments the viscous aqueous or nonaqueous fluid canhave a viscosity at 20° C. of at least about 30 cp, e.g., about 40 cp,about 50 cp, about 60 cp, at least about 40 cp, at least about 50 cp, orat least about 60 cp. In a preferred embodiment, the pharmaceuticalcomposition releases an effective amount of the active agent (one ormore of the pamoate salts of the monoamine agents as described herein)over a period of at least about 24 hours or at least about 48 hours. Inanother preferred embodiment, the active agent in the pharmaceuticalcomposition has a duration of efficacy of at least about 7 days or atleast about 14 days.

The invention further relates to methods of treating a subject havingsyndrome associated with Parkinson's disease, such as a warm bloodmammal (such as a human patient or subject characterized as havingParkinson's disease). The method comprises administering atherapeutically effective amount of a pharmaceutical compositioncomprising a pamoate salt of the monoamine agent (e.g., any of thosedescribed herein) and at least one pharmaceutically acceptable carrier.

In various embodiments, the present inventor discovered that thepharmaceutically acceptable salts of the monoamine agents formed usingpamoic acid as a counterion surprisingly exhibit very low solubility(K_(T)). This low solubility can be highly desirable when used in apharmaceutical composition to provide for extended release of thepamoate salt of the monoamine agents, for example, when administeredintramuscularly or subcutaneously. In some embodiments, thepharmaceutical compositions of the present invention include variouspharmaceutical dosage forms for the purposes of administering dosage toa subject (such as a warm blooded mammal, such as a human) in need oftreatment of Parkinson's disease. In some embodiments, to prepare thepharmaceutical compositions of the present invention, a pharmaceuticallyeffective amount of one or more pamoate salts of the monoamine agent (asthe active ingredient or active agent) are combined with one or morepharmaceutically acceptable excipients. The pharmaceutically acceptableexcipients used are generally less critical, are well known in the art,and may take a wide variety of forms depending on the form ofpreparation desired for administration. In some embodiments, thesepharmaceutical compositions are provided in a unit dosage form suitablefor administration.

Administration of the compositions of the present invention can be, forexample, parenterally, such as by subcutaneous or intramuscularinjection or implantation. For administration, the pamoate salts of themonoamine agents can be, for example, suspended in an aqueous solvent,which can further comprise a wetting agent, such as the polyoxyethylenederivatives of sorbitan esters, e.g. polysorbate 80 (Tween® 80) andpolysorbate 20 (Tween® 20), lecithin, polyoxyethylene- andpolyoxypropylene ethers, sodium deoxycholate, and the like; a suspendingagent such as a cellulose derivate, e.g. methylcellulose, sodiumcarboxymethylcellulose and hydroxypropyl methylcellulose,polyvinylpyrrolidone, alginates, chitosan, dextran, gelatin,polyethylene glycols, polyoxyethylene- and polyoxypropylene ethers andthe like; an acid, e.g. hydrochloric acid, and the like; a base, e.g.sodium hydroxide, and the like; a buffer comprising a mixture ofappropriate amounts of an acid such as phosphoric, succinic, tartaric,lactic, acetic, maleic or citric acid, and a base, in particular sodiumhydroxide or disodium hydrogen phosphate; a preservative, e.g. benzoicacid, benzyl alcohol, butylated hydroxyanisole, butylatedhydroxytoluene, chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol,chlorocresol, metacresol, benzothonium chloride,myristyl-.gamma.-piccolinium chloride, phenylmercuri acetate, thimerosaland the like; a tonicity adjusting agent, e.g. sodium chloride,dextrose, mannitol, sorbitol, lactose, sodium sulfate, and the like. Insome embodiments, the pamoate salts of the monoamine agents can also beformulated in one or more oils. Appropriate oils that can be usedinclude fixed oils, for example, peanut oil, sesame oil, cottonseed oil,corn oil, safflower oil, castor oil, ethyloleate, soybean oil, syntheticglycerol esters of long chain fatty or medium chain acids and mixturesof these and other oils. In some embodiments, thickening agents can beadded to the composition, e.g. aluminum monostearate, ethylcellulose,triglycerides, hydrogenated castor oil, and the like.

In view of the usefulness of the pamoate salts of the monoamine agentsin the treatment of Parkinson's diseases, in some embodiments, thepresent invention further provides a method of treating warm-bloodedmammals (such as humans), suffering from PD. In some embodiments, themethod comprises administering a therapeutically effective amount of apharmaceutical composition comprising at least one pamoate salt of themonoamine agents as described herein and one or more pharmaceuticallyacceptable excipients.

In some embodiments, the pharmaceutical compositions described hereincan be administered to a subject in need of treatment of Parkinson'sdisease as a long acting composition. In one embodiment, the activeagent is released from the composition over a period of at least about24 hours, preferably at least about 48 hours. The active agent can alsobe administered in an extended release composition. In one embodiment,the extended release composition releases the active agent over a periodof at least about 7 days, preferably at least about 14 days,alternatively for at least 2 weeks, at least 3 weeks, at least 4 weeks,at least 6 weeks or at least 8 weeks. The composition can beadministered by injection, such as intramuscularly or subcutaneously. Inone embodiment, the compositions can be administered as a single or soledose. However, in some embodiments, the compositions described hereinare particularly beneficial for those subjects in need of treatment ofParkinson's disease that require constant or chronic therapy, such asthose subjects that receive repeated doses over several weeks or monthsor more. In such dosing regimens, the method can comprise: (1)administering as first dose an first extended release compositioncontaining one or more of the pamoate salts of the monoamine agents asdescribed herein followed by (2) administering as a second dose (and assubsequence doses if necessary), a second extended release composition.The second extended release composition can be the same, substantiallythe same or different than the first extended release composition.Specifically, in some embodiments, the second extended releasecomposition can include as the active agent of one or more of thepamoate salts of the monoamine agents as described herein or an activeagent that is other than the pamoate salts of the monoamine agents asdescribed herein. The second composition can be administered at about 7days, or more, such as at least about 14 days, or at least about 21days, after the first administration of the first extended releasecomposition, where the first administration results in the release ofactive agent for a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14days, or more.

As used herein, the term “about” modifying an amount related to theinvention refers to variation in the numerical quantity that can occur,for example, through routine testing and handling; through inadvertenterror in such testing and handling; through differences in themanufacture, source, or purity of ingredients employed in the invention;and the like. As used herein, “about” a specific value also includes thespecific value, for example, about 10% includes 10%. Whether or notmodified by the term “about”, the claims include equivalents of therecited quantities. In one embodiment, the term “about” means within 20%of the reported numerical value.

As used herein, the term “individual”, “subject” or “patient” refers toa warm blooded animal which is afflicted with a particular diseasestate. Warm blooded animals include mammals, such as humans.

The term “effective amount” or “therapeutically effective amount” isdefined as an amount resulting in the improvement of any parameters orclinical symptoms. In any of the embodiments described in, the term“effective amount” or “therapeutically effective amount” can be anamount resulting in the improvement of any parameters or clinicalsymptoms associated with Parkinson's disease. The actual dose may varywith each patient and does not necessarily indicate a total eliminationof all disease symptoms. A therapeutically effective amount of thecompound used in the methods described herein can be readily determinedby one skilled in the art, such as an attending physician, by observingresults obtained under analogous circumstances and by using conventionaltechniques. In determining the therapeutically effective dose, theattending physician considers a number of factors, including, but notlimited to: the species of mammal; its size, age, and general health;the specific disease involved; the degree of involvement or the severityof the disease; the response of the individual patient; the particularcompound administered; the mode of administration; the bioavailabilitycharacteristic of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances.

Similarly, the term “duration of efficacy” or “therapeutically effectiveplasma concentration” of a monoamine for a given time period should beunderstood as such that during such time period, the respectivemonoamine is present (e.g., in the plasma of a subject treated with thepamoate salt herein) in an amount and/or concentration sufficient toresult in the improvement of any parameters or clinical symptoms, forexample, the improvement of any parameters or clinical symptomsassociated with Parkinson's disease.

Preferred amounts and modes of administration can be readily bedetermined by one skilled in the art depending upon the particularcharacteristics of the compound selected, the disease state to betreated, the stage of the disease, and other relevant circumstancesusing formulation technology known in the art, described for example inRemington's Pharmaceutical Sciences, latest edition, Mack Publishing Co.

Pharmaceutical compositions can be manufactured utilizing routinetechniques known in the art. Typically a therapeutically effectiveamount of the compound (salt) will be combined with a pharmaceuticallyacceptable carrier.

The pharmaceutical compositions of the present invention can beadministered parenterally. For instance, they can be administered byinjection. Preferred methods of parenteral administration includeintramuscular and subcutaneous injection.

For parenteral administration, the compounds (salt) can be dissolved ina physiologically acceptable pharmaceutical carrier and administered aseither a solution or a suspension. Viscous injectable carriers arepreferred, having for example, a viscosity of at least 20 cp at 20° C.In other embodiments, the fluid phase of the suspension has a viscosityat 20° C. of at least about 30 cp, e.g., about 40 cp, about 50 cp, about60 cp, at least about 40 cp, at least about 50 cp, or at least about 60cp. The composition can also comprise a viscosity enhancing agent, adensity enhancing agent, a tonicity enhancing agent, and/or a wettingagent. Suitable pharmaceutical carriers include water, saline, dextrosesolutions, fructose solutions, ethanol, or oils of animal, vegetative,or synthetic origin. The pharmaceutical carrier may also containpreservatives, and buffers as known in the art.

When the composition is to be used as an injectable material, including,but not limited to, needle-less injection, it can be formulated into aconventional injectable carrier. Suitable carriers include biocompatibleand pharmaceutically acceptable solutions, emulsions or suspensions.

In another embodiment, the formulation can be surgically implanted. Suchformulations can include any of the well-known biodegradable andbioerodible carriers, such as polylactides, poly-lactide-co-glycolidesand collagen formulations. Such materials can be in the form of solidimplants, sponges, and the like. In any event, for local use of thematerials, the active ingredients usually are present in the carrier orexcipient in a weight ratio of from about 1:1000 to 1:20,000, but arenot limited to ratios within this range.

In some embodiments, the present invention also provides methods ofmaking pamoate salts of the monoamine agents. Specifically, pamoatesalts of the monoamine agents can be prepared in a variety of differentways. For example, in one embodiment, pamoate salts of the monoamineagents can be prepared directly by treating or mixing the monoamineagents (such as a free base) with pamoic acid in a solvent (such aswater, ethanol or DMSO). In another embodiment, pamoate salts of themonoamine agents can be prepared by treating or mixing the monoamineagents salt (such as a hydrochloride salt) with a pamoate salt (such asdisodium pamoate) in one or more solvents. For example, the pamoate ofthe monoamine agents can be prepared by adding a solution of disodiumpamoate, or other pamoate salt in an appropriate solvent, such as water,to a solution of the monoamine agent hydrochloride and leaving thesolution to stir for a period of time, such as, for example, about 3 or12 hours, until precipitation occurs. Alternatively, other methods suchas evaporation, slurry, anti-solvent, cooling and hydration can also beused to crystalize the salt. Solvents useful for preparing the pamoatesalts herein include, without limitation, water, alkanols (e.g. methanoland ethanol), alkyl ketones (e.g. acetone), alkanes (e.g. n-heptane),acetonitrile, toluene, DMSO, alkyl ester (e.g. ethyl acetate),halogenated alkanes (e.g. chloroform), ethers, tetrahydrofuran (THF),1,4-dioxane, and combinations thereof.

In some embodiments, the present invention provides a solid state formof pharmaceutical acceptable salt of dopamine agonists rotigotine,ropinirole, and pramipexole, wherein the salt is a pamoate salt. Thepamoate salt can be crystalline, anhydrous, hydrated, solvated, oramorphous. In another embodiment, the invention relates to crystallinepamoate salts of rotigotine, ropinirole, or pramipexole having orcharacterized by one or more of the following properties: (1) an X-raypowder diffraction pattern substantially in accordance with those shownin FIGS. 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, respectively, for eachcrystalline form; (2) a differential scanning calorimetry thermogrampattern substantially in accordance with those shown in FIGS. 2, 4, 6,8, 10, 12, 14, 16, 18, 20, respectively, for each crystalline form; and(3) a combination of (1) and (2). In some embodiments, the presentinvention also relates to compositions containing one or more of theabove described pamoate salts of rotigotine, ropinirole, and pramipexoleand pharmaceutical compositions containing said compositions and atleast one pharmaceutically acceptable carrier.

In some embodiments, the present invention provides a solid state formof a pharmaceutical acceptable salt of anti-PD MAO-B inhibitorsselegiline, rasagiline, and safinamide, wherein the salt is a pamoatesalt. The pamoate salt can be crystalline, anhydrous, hydrated,solvated, or amorphous. In some embodiments, the present invention alsoprovides compositions containing one or more of the above describedpamoate salts of selegiline, rasagiline, and safinamide andpharmaceutical compositions containing said compositions and at leastone pharmaceutically acceptable carrier.

The following examples are intended to illustrate and not to limit thescope of the present invention.

EXAMPLES Example 1

Preparation of Ropinirole Pamoate at a 1:1 Molar Ratio of Ropinirole toPamoic Acid from a Mixture of DMSO and Water.

Ropinirole (2 g, 7.7 mmol) and Pamoic Acid (2.975 g, 7.7 mmol) was addedinto DMSO (15 mL) with stirring to form a solution. The resultantsolution was slowly added to water (500 mL) at room temperature whichproduced a white solid. The solid was collected on a filter, washed withwater, and dried in vacuum at 40° C. to generate Ropinirole Pamoate aswhite solids (4.0 g, 80.4%).

X-ray powder diffraction (“XRPD”) patterns of above solids were obtainedusing a Bruker D8 Advance x-ray powder diffractometer with copper Kαradiation at a wavelength of 1.54 nm. Instrumental conditions included astep size of 0.02 degree per step, a scan rate of 0.2 seconds per step,a 2-theta range of 3 to 40 degrees, a voltage of 40 kV, a current of 40mA, and a Lynxeye detector. Samples were packed into recessed sampleholders for analysis. Typically, the error margin for 2-theta values is±0.2°. XRPD patterns for other examples herein were obtained similarly.A typical example of X-ray powder diffraction pattern and data,respectively, for the salt from Example 1 is shown in FIG. 1 and Table 1wherein d(A) represents the interplanar spacing. Height and Height %represent the typical relative intensities.

The differential scanning calorimetry thermogram of above solids wasobtained using a TA Instrument Q200 Differential Scanning calorimeter.The measurement was controlled by “Thermal Advantage” system and datawas analyzed using “Universal Analysis” software. Typical sample loadranges from 0.5 to 5 mg. The measurement is under an atmosphere ofnitrogen with flow rate of 40 mL/min. System equilibrium is set at 20°C. and the temperature is then increased to 250° C. at a rate of 10°C./min. Typically, the error margin for DSC peak values is ±3° C. DSCthermograms for other examples herein were obtained similarly. A typicalexample of a differential scanning calorimetry thermogram for the saltfrom Example 1 is shown in FIG. 2. ¹H NMR (see FIG. 23) indicates thatthe molar ratio of Ropinirole to Pamoic Acid in the salt from Example 1is about 1:1.

TABLE 1 2-Theta d(A) Height Height % 4.279 20.6311 489 100.0 8.50810.3844 131 26.8 9.750 9.0644 370 75.7 10.479 8.4352 236 48.3 11.5237.6727 288 58.9 12.096 7.3111 134 27.4 12.748 6.9386 140 28.6 13.8456.3908 145 29.7 14.363 6.1616 316 64.6 15.971 5.5446 319 65.2 16.5045.3669 173 35.4 17.126 5.1732 461 94.3 17.608 5.0326 121 24.7 18.6484.7543 400 81.8 19.146 4.6317 382 78.1 19.615 4.5222 78 16.0 20.4674.3357 396 81.0 21.007 4.2255 369 75.5 21.553 4.1196 103 21.1 22.4713.9533 62 12.7 23.111 3.8452 369 75.5 23.831 3.7307 274 56.0 24.3283.6556 142 29.0 25.517 3.4879 173 35.4 26.052 3.4174 90 18.4 26.4503.3670 342 69.9 26.910 3.3105 259 53.0 29.473 3.0281 207 42.3 29.9142.9844 75 15.3 30.686 2.9112 55 11.2 31.494 2.8382 45 9.2 34.235 2.617042 8.6 38.553 2.3333 44 9.0

Example 2

Preparation of Ropinirole Pamoate at a 1:1 Molar Ratio of Ropinirole toPamoic Acid from Heating Batches Depicted in FIGS. 1 and 2 at 170° C.for 30 Minutes

75 mg of ropinirole pamoate from Example 1 was placed at 170° C. for 30minutes to give a solid of which a typical example of an X-raydiffraction pattern is shown in FIG. 3 and Table 2. A typical example ofa differential scanning calorimetry thermogram for this solid is shownin FIG. 4. ¹H NMR indicates that the molar ratio of Ropinirole to PamoicAcid in this solid is about 1:1.

TABLE 2 2-Theta d(A) Height Height % 9.402 9.3986 185 54.9 11.082 7.9772144 42.7 11.460 7.7152 307 91.1 12.004 7.3667 262 77.7 12.683 6.9738 23569.7 13.290 6.6567 85 25.2 14.287 6.1942 138 40.9 15.549 5.6942 190 56.416.406 5.3988 298 88.4 17.209 5.1485 185 54.9 18.652 4.7532 187 55.519.367 4.5794 136 40.4 19.846 4.4698 112 33.2 20.145 4.4044 155 46.021.009 4.2251 315 93.5 21.367 4.1550 121 35.9 22.368 3.9713 151 44.823.051 3.8552 297 88.1 23.410 3.7969 337 100.0 24.172 3.6788 85 25.224.525 3.6267 62 18.4 25.570 3.4808 70 20.8 25.951 3.4306 110 32.626.228 3.3949 269 79.8 26.872 3.3150 150 44.5 27.768 3.2101 96 28.529.836 2.9922 117 34.7 30.898 2.8917 40 11.9 36.518 2.4585 38 11.338.074 2.3616 39 11.6

Example 3

Preparation of Ropinirole Pamoate at a 2:1 Molar Ratio of Ropinirole toPamoic Acid from a Mixture of Ethanol, Water and PEG6000.

100 mg of ropinirole pamoate from Example 1 was dissolved at roomtemperature in a mixture of 14 mL of ethanol and 7 mL of water. To thesolution was added 10% PEG6000 and the resultant mixture was dissolvedby sonication which was then concentrated at 40° C., which produced asolid. This solid was then collected, washed, and dried. A typicalexample of an X-ray diffraction pattern for this solid is shown in FIG.5 and Table 3. A typical example of a differential scanning calorimetrythermogram for this solid is shown in FIG. 6. ¹H NMR (see FIG. 24)indicates that the molar ratio of Ropinirole to Pamoic Acid in the saltfrom Example 3 is about 2:1.

TABLE 3 2-Theta d(A) Height Height % 8.026 11.0074 362 24.9 9.501 9.3008205 14.1 10 707 8.2559 71 4.9 11.275 7.8414 92 6.3 11.837 7.4700 96 6.612.103 7.3067 127 8.7 13.387 6.6084 166 11.4 15.666 5.6521 170 11.716.073 5.5097 1227 84.5 16.844 5.2591 50 3 4 17.166 5.1613 87 6.0 17.6725.0147 48 3.3 18.219 4.8653 89 6.1 18.773 4.7229 1452 100.0 20.3944.3511 94 6.5 21.158 4.1957 147 10.1 21.479 4.1336 177 12.2 22.3593.9729 47 3.2 23.052 3.8550 53 3.7 24.391 3.6463 78 5.4 25.100 3.5449148 10.2 25.914 3.4354 54 3.7 26.277 3.3888 116 8.0 26.913 3.3101 60 4.127.613 3.2278 60 4.1 29.967 2.9794 68 4.7 32.473 2.7549 91 6.3 35.3282.5385 45 3.1

Example 4

Preparation of Ropinirole Pamoate at a 1:1 Molar Ratio of Ropinirole toPamoic Acid from a Mixture of DMSO and Acetonitrile.

100 mg of ropinirole pamoate from Example 1 was dissolved in 0.45 mL ofdimethyl sulfoxide (DMSO). To the solution at room temperature was added5 mL of acetonitrile. The resultant solution was then stirred at 4° C.to yield a solid, which was collected, washed, and dried. A typicalexample of an X-ray diffraction pattern for this solid is shown in FIG.7 and Table 4. A typical example of a differential scanning calorimetrythermogram for this solid is shown in FIG. 8. ¹H NMR indicates that themolar ratio of Ropinirole to Pamoic Acid in this solid is about 1:1.

TABLE 4 2-Theta d(A) Height Height % 9.426 9.3748 51 9.5 14.304 6.1868129 24.0 16.106 5.4985 45 8.4 17.889 4.9544 538 100.0 18.848 4.7044 7714.3 19.386 4.5750 59 11.0 21.453 4.1386 96 17.8 21.930 4.0496 65 12.122.370 3.9710 89 16.5 24.815 3.5850 102 19.0 25.248 3.5244 179 33.325.562 3.4819 56 10.4 28.168 3.1654 44 8.2 32.076 2.7881 39 7.2 32.4362.7579 74 13.8

Example 5

Preparation of Ropinirole Pamoate at a 2:1 Molar Ratio of Ropinirole toPamoic Acid from a Mixture of Ethanol, Water and Poly(AllylamineHydrochloride).

100 mg of ropinirole pamoate from Example 1 was dissolved in a mixtureof 14 mL of ethanol and 7 mL of water. To the solution was added 10%poly(allylamine hydrochloride). After kept evaporation at 40° C., asolid was formed and characterized by XRPD and DSC. A typical example ofan X-ray diffraction pattern for this solid is shown in FIG. 9 and Table5. A typical example of a differential scanning calorimetry thermogramfor this solid is shown in FIG. 10. ¹H NMR indicates that the molarratio of Ropinirole to Pamoic Acid in this solid is about 2:1.

TABLE 5 2-Theta d(A) Height Height % 7.281 12.1314  166 31.9 9.3429.4591 159 30.5 10.346 8.5428 88 16.9 11.122 7 9490 365 70.1 11.6857.5671 434 83.3 11.965 7.3905 521 100.0 12.783 6.9195 165 31.7 13.3486.6279 99 19.0 14.800 5.9807 219 42.0 15.506 5.7099 289 55.5 15.948 55527 202 38.8 16.711 5.3007 122 23.4 16.992 5.2138 204 39.2 18.0804.9024 109 20.9 18.807 4.7144 286 54.9 19.217 4.6149 95 18.2 19.6124.5227 284 54.5 20.210 4.3902 260 49.9 21.009 4.2250 398 76.4 22.1914.0027 165 31.7 22.571 3.9361 169 32.4 22.911 3.8785 267 51.2 23.6293.7622 280 53.7 24.214 3 6726 185 35.5 24.691 3.6027 95 18.2 24.9683.5633 199 38.2 25.791 3.4515 182 34.9 26.130 3.4075 320 61.4 26.6363.3439 353 67.8 27.033 3.2957 77 14.8 27.458 3.2456 137 26.3 28.2513.1563 46 8.8 29.223 3.0535 45 8.6 29.753 3.0003 150 28.8 32.523 2.750861 11.7 33.756 2.6530 61 11.7 34.561 2.5931 41 7.9 35.045 2.5584 50 9.637.818 2.3769 188 36.1 38.437 2.3400 38 7.3

Example 6

Preparation of Rotigotine Pamoate at a 1:1 Molar Ratio of Rotigotine toPamoic Acid from a Mixture of Ethanol, Acetone, and n-Heptane.

35.2 mg of rotigotine hydrochloride salt was dissolved in a mixture of 4mL of acetone and 1 mL of ethanol via sonication. Separately, 41 mg ofsodium pamoate was dissolved in a mixture of 2 mL of ethanol and 0.4 mLof acetone. To the rotigotine hydrochloride solution was added in adropwise manner the sodium pamoate solution. After addition and stirredfor 30 minutes, 4 mL of n-heptane was added and the resultant solutionwas stirred overnight to generate rotigotine pamoate as crystallinesolid. The solid was collected, washed with water, dried under vacuum,and characterized by XRPD and DSC. A typical example of an X-raydiffraction pattern for this solid is shown in FIG. 11 and Table 6. Atypical example of a differential scanning calorimetry thermogram forthis solid is shown in FIG. 12. ¹H NMR (see FIG. 25) indicates that themolar ratio of Rotigotine to Pamoic acid in this solid is about 1:1.

TABLE 6 2-Theta d(A) Height Height % 4.600 19.1958 1736 100.0 8.67410.1855 124 7.1 9.284 9.5181 935 53.9 10.499 8.4193 68 3.9 11.105 7.960885 4.9 13.985 6.3274 105 6.0 14.678 6.0301 78 4.5 16.619 5.3298 71 4.117.000 5.2113 55 3.2 17.468 5.0728 321 18.5 17.883 4.9559 58 3.3 18.6814.7459 251 14.5 19.040 4.6572 166 9.6 20.480 4.3330 121 7.0 20.7224.2829 118 6.8 21.641 4.1031 94 5.4 22.506 3.9473 199 11.5 23.220 3.8275103 5.9 23.543 3.7757 96 5.5 24.248 3.6675 270 15.6 25.230 3.5269 95 5.525.556 3.4827 117 6.7 25.961 3.4293 189 10.9 26.403 3.3729 317 18.327.754 3.2116 71 4.1 28.186 3.1634 270 15.6 29.587 3.0167 257 14.830.919 2.8897 87 5.0 31.545 2.8338 73 4.2 33.903 2.6419 74 4.3 34.9782.5631 56 3.2 37.465 2.3985 40 2.3

Example 7

Preparation of Pramipexole Pamoate at a 1:1 Molar Ratio of Pramipexoleto Pamoic Acid from a Mixture of Acetone and Water.

Pramipexole (3.0 g, 14.1 mmol) and Pamoic acid (2.7 g, 7.0 mmol) wasdissolved by stirring at room temperature in DMSO (30 mL). The solutionwas then slowly added to ethyl acetate (2 L) at room temperature togenerate a white solid. The solid was collected on a filter and dried invacuum at 45° C. to give an amorphous pramipexole pamoate at a 2:1 Molarratio of Pramipexole to Pamoic acid (4.5 g, 78.6%).

100 mg of above amorphous pramipexole pamoate salt was dissolved in amixture of 3 mL of acetone and 0.5 mL of water at 60° C. The solutionwas slowly cooled to room temperature and stirred for 3 hours to yieldpramipexole pamoate as a solid, which was collected, washed, and dried.The solid was characterized by XRPD and DSC. A typical example of anX-ray diffraction pattern for this solid is shown in FIG. 13 and Table7. A typical example of a differential scanning calorimetry thermogramfor this solid is shown in FIG. 14. ¹H NMR (see FIG. 21) indicates thatthe molar ratio of Pramipexole to Pamoic acid in this solid is about1:1.

TABLE 7 2-Theta d(A) Height Height % 7.659 11.5328 153 24.2 11.8177.4826 157 24.8 12.130 7.2905 56 8.9 13.843 6.3920 354 56.0 15.3035.7852 632 100.0 16.796 5.2741 72 11.4 17.285 5.1259 64 10.1 18.0204.9186 64 10.1 18.903 4.6908 159 25.2 21.141 4.1989 595 94.1 23.0823.8502 194 30.7 23.680 3.7541 136 21.5 25.542 3.4846 83 13.1 26.4213.3706 135 21.4 27.904 3.1948 50 7.9 30.109 2.9656 52 8.2 30.682 2.911553 8.4

Example 8

Preparation of Pramipexole Pamoate at a 1:1 Molar Ratio of Pramipexoleto Pamoic Acid from a Mixture of Acetone and Methanol.

100 mg of amorphous pramipexole pamoate salt from Example 7 wasdissolved in 0.6 mL of methanol at room temperature. To the solution wasadded 3 mL of acetone with stirring to yield pramipexole pamoate as acrystalline solid, which was collected, washed, and dried. The solid wascharacterized by XRPD and DSC. A typical example of an X-ray diffractionpattern for this solid is shown in FIG. 15 and Table 8. A typicalexample of a differential scanning calorimetry thermogram for this solidis shown in FIG. 16. ¹H NMR indicates that the molar ratio ofPramipexole to Pamoic acid in this solid is about 1:1.

TABLE 8 2-Theta d(A) Height Height % 7.416 11.9106 85 26.8 11.421 7.741687 27.4 11.740 7.5317 100 31.5 12.043 7.3428 235 74.1 13.378 6.6128 8326.2 14.999 5.9018 317 100.0 16.417 5.3949 69 21.8 17.243 5.1383 11536.3 17.698 5.0074 71 22.4 18.595 4.7677 72 22.7 19.704 4.5017 93 29.320.022 4.4310 79 24.9 20.364 4.3574 239 75.4 20.905 4.2459 188 59.322.480 3.9518 151 47.6 23.302 3.8143 149 47.0 23.579 3.7701 65 20.524.202 3.6743 68 21.5 25.424 3.5005 123 38.8 25.881 3.4397 47 14.827.406 3.2517 59 18.6 29.398 3.0357 50 15.8 31.368 2.8494 37 11.7 33.7122.6564 34 10.7 34.525 2.5957 34 10.7

Example 9

Preparation of Pramipexole Pamoate at a 2:1 Molar Ratio of Pramipexoleto Pamoic Acid from a Solution of Ethyl Acetate.

50 mg of amorphous pramipexole pamoate salt from Example 7 was dissolvedin 2.5 mL of ethyl acetate. The solution was stirred for 5 days at roomtemperature to yield pramipexole pamoate as a solid, which wascollected, washed, and dried. The solid was characterized by XRPD andDSC. A typical example of an X-ray diffraction pattern for this solid isshown in FIG. 17 and Table 9. A typical example of a differentialscanning calorimetry thermogram for this solid is shown in FIG. 18. ¹HNMR (see FIG. 26) indicates that the molar ratio of Pramipexole toPamoic acid in this solid is about 2:1.

TABLE 9 2-Theta d(A) Height Height % 6.051 14.5950 100 26.2 9.181 9.624181 21.2 10.227 8.6423 100 26.2 10.681 8.2760 261 68.3 11.018 8.0235 11229.3 12.683 6.9736 225 58.9 13.523 6.5426 382 100.0 14.942 5.9241 27772.5 16.276 5.4416 166 43.5 17.243 5.1385 101 26.4 18.062 4.9073 18347.9 18.681 4.7460 207 54.2 19.957 4.4454 138 36.1 20.483 4.3324 14337.4 21.780 4.0771 95 24.9 22.325 3.9790 212 55.5 22.766 3.9028 134 35.123.644 3.7598 66 17.3 24.820 3.5843 73 19.1 25.566 3.4814 106 27.727.479 3.2432 56 14.7 28.900 3.0868 68 17.8

Example 10

Preparation of Pramipexole Pamoate at a 2:1 Molar Ratio of Pramipexoleto Pamoic Acid from a Solution of Tetrahydrofuran

50 mg of amorphous pramipexole pamoate salt from Example 7 was dissolvedin 2.5 mL of tetrahydrofuran (THF). The solution was stirred for 10 daysat room temperature to yield pramipexole pamoate as a solid, which wascollected, washed, and dried. The solid was characterized by XRPD andDSC. A typical example of an X-ray diffraction pattern for this solid isshown in FIG. 19 and Table 10. A typical example of a differentialscanning calorimetry thermogram for this solid is shown in FIG. 20. ¹HNMR (see FIG. 22) indicates that the molar ratio of Pramipexole toPamoic acid in this solid is about 2:1.

TABLE 10 2-Theta d(A) Height Height % 6.096 14.4874 773 45.0 11.0188.0238 341 19.9 11.563 7.6469 400 23.3 12.164 7.2701 177 10.3 12.4217.1200 221 12.9 13.539 6.5348 458 26.7 14.856 5.9582 449 26.2 16.2895.4373 167 9.7 17.883 4.9559 1717 100.0 18.903 4.6908 558 32.5 19.2274.6125 141 8.2 19.546 4.5379 313 18.2 20.500 4.3288 175 10.2 21.2864.1707 617 35.9 21.799 4.0736 425 24.8 22.441 3.9586 428 24.9 23.2083.8294 683 39.8 23.625 3.7628 291 16.9 24.024 3.7013 529 30.8 24.9593.5646 197 11.5 26.313 3.3842 152 8.9 26.799 3.3239 132 7.7 27.2403.2711 192 11.2 27.820 3.2042 130 7.6 28.887 3.0882 109 6.3 29.4883.0267 67 3.9 30.072 2.9692 54 3.1 30.643 2.9151 196 11.4 31.409 2.8458114 6.6 32.287 2.7704 49 2.9 34.501 2.5974 151 8.8 35.565 2.5221 59 3.435.925 2.4977 61 3.6 36.968 2.4296 89 5.2 38.144 2.3574 112 6.5 38.6772.3261 47 2.7

Example 11

Characterization of Pramipexole Pamoates at a 1:1 or 2:1 Molar Ratio ofPramipexole to Pamoic Acid by Proton Nuclear Magnetic ResonanceSpectroscopy (¹H-NMR).

Pramipexole pamoates (1:1 and 2:1) were analyzed using ¹H-NMR. The¹H-NMR spectra are provided in FIGS. 21 and 22. FIG. 21 is the ¹H-NMRspectrum of the 1:1 salt prepared from a mixture of acetone and water(Example 7). The molar ratio of pramiperxol to pamoic acid wasapproximately 1:1 measured from proton integration of the ¹H NMRspectrum. ¹H NMR (500 MHz, DMSO-d₆) chemical shifts were recorded at(all values in ppm) 8.65 (b, 2H), 8.28 (s, 2H), 8.17 (d, 2H), 7.73 (d,2H), 7.21 (t, 2H), 7.09 (t, 2H), 6.84 (s, 2H), 4.72 (s, 2H), 3.49 (m,3H), 2.97 (m, 3H), 2.50-2.68 (m, 6H), 2.17 (m, 1H), 1.83 (m, 1H), 1.65(m, 2H), 0.94 (t, 3H). FIG. 22 is the ¹H-NMR spectrum of the 2:1 saltprepared in a solution of tetrahydrofuran (Example 10). The molar ratioof pramipexole to pamoic acid was approximately 2:1 measured from protonintegration of the ¹H-NMR spectrum. ¹H-NMR (500 MHz, DMSO-d₆) chemicalshifts were recorded at (in ppm) 8.65 (b, 2H), 8.19 (m, 2H), 7.63 (d,1H), 7.11 (m, 1H), 6.99 (m, 1H), 6.78 (s, 2H), 4.67 (s, 1H), 3.59 (m,2H), 3.49 (m, 1H), 2.97 (m, 3H), 2.50-2.68 (m, 3H), 2.17 (m, 1H),1.51-1.83 (m, 5H), 1.65 (m, 2H), 0.95 (t, 3H).

Example 12

Crystalline Form Screening of Pramipexole Pamoate Salt Using DifferentSolvent Systems.

This example provides a crystalline form screening summary of thepramipexole pamoate salt described in the above examples. The solventused to prepare the crystalline form of pramipexole pamoate can beimportant as many solvents or solvent system did not work for theformation of crystalline salt form.

A panel of solvents or the combination of these solvents includingwater, alkanols (e.g. methanol and ethanol), alkyl ketones (e.g.acetone), alkanes (e.g. n-heptane), acetonitrile, toluene, DMSO, alkylester (e.g. ethyl acetate), halogenated alkanes (e.g. chloroform), THF,and 1,4-dioxane were screened to generate the crystalline form of thepramipexole pamoate salt. Using these solvents, different types ofcrystallization techniques known by one in the art were used includingcooling, evaporation, and addition of a second solvent to reduce thesolubility of the solute (technique known as anti-solvent or drown-out).

When a mixture of acetone and water or a mixture of acetone and methanolwas used as solvent system, two different crystalline forms of amono-pramipexole pamoate salt were obtained using amorphous pramipexolepamoate salt as depicted in Examples 7 and 8. However, as described inExamples 9 and 10, two different crystalline forms of a semi-pramipexolepamoate salt were obtained from amorphous pramipexole pamoate salt whenusing ethyl acetate or tetrahydrofuran (THF) as solvent system.

Between two crystalline forms of mono-pramipexole pamoate salt obtainedusing the above solvent systems, the form that was obtained from acetoneand water in Example 7 is more stable. The form from Example 8 startedconverting into the crystalline form depicted in Example 7 upon standingat room temperature after 7 days. For the two crystalline forms ofsemi-pramipexole pamoate salt, the form described in Example 10 was morestable. The crystalline form of semi-pramipexole pamoate salt fromExample 9 was converting into amorphous state when placed in the dry boxat room temperature.

Example 13

Preparation of Ropinirole Pamoate at a 2:1 Molar Ratio of Ropinirole toPamoic Acid from a Mixture of DMSO and Water.

Ropinirole (1.3 g, 5 mmol) and Pamoic Acid (0.967 g, 2.5 mmol) was addedinto DMSO (8 mL) with stirring to form a solution. The resultantsolution was slowly added to water (250 mL) at room temperature whichproduced a white solid. The solid was collected on a filter, washed withwater, and dried in vacuum at 45° C. to generate Ropinirole Pamoate aswhite solids (2.1 g, 92.6%).

Example 14

A. Preparation of Rotigotine Pamoate at a 1:1 Molar Ratio of Rotigotineto Pamoic Acid from a Mixture of DMSO and Water.

Rotigotine (3 g, 9.51 mmol) and Pamoic Acid (3.68 g, 9.51 mmol) wasadded into DMSO (40 mL) with stirring to form a solution. The resultantsolution was slowly added to water (500 mL) at room temperature whichproduced a white solid. The solid was collected on a filter, washed withwater, and dried in vacuum at 45° C. to generate Rotigotine Pamoate aswhite solids (5 g, 74.9%).

B. Preparation of Rotigotine Pamoate at a 2:1 Molar Ratio of Rotigotineto Pamoic Acid from a Mixture of DMSO and Water.

Rotigotine (1 g, 3.17 mmol) and Pamoic Acid (0.614 g, 1.585 mmol) wasadded into DMSO (8 mL) with stirring to form a solution. The resultantsolution was slowly added to water (500 mL) at room temperature whichproduced a white solid. The solid was collected on a filter, washed withwater, and dried in vacuum at 45° C. to generate Rotigotine Pamoate aswhite solids (2 g, 77.4%).

Example 15

Preparation of Pramipexole Pamoate at a 1:1 Molar Ratio of Pramipexoleto Pamoic Acid from a Mixture of DMSO and Ethyl Acetate (EA).

Pramipexole (5.0 g, 23.44 mmol) and Pamoic acid (9.08 g, 23.44 mmol) wasdissolved by stirring at room temperature in DMSO (50 mL). The solutionwas then slowly added to ethyl acetate (2 L) at room temperature togenerate a white solid. The solid was collected on a filter and dried invacuum at 45° C. to give pramipexole pamoate at a 1:1 Molar ratio ofPramipexole to Pamoic acid (14.0 g, 99.0%).

It is to be appreciated that the Detailed Description section, and notthe Summary and Abstract sections, is intended to be used to interpretthe claims. The Summary and Abstract sections may set forth one or morebut not all exemplary embodiments of the present invention ascontemplated by the inventor(s), and thus, are not intended to limit thepresent invention and the appended claims in any way.

The present invention has been described above with the aid offunctional building blocks illustrating the implementation of specifiedfunctions and relationships thereof. The boundaries of these functionalbuilding blocks have been arbitrarily defined herein for the convenienceof the description. Alternate boundaries can be defined so long as thespecified functions and relationships thereof are appropriatelyperformed.

With respect to aspects of the invention described as a genus, allindividual species are individually considered separate aspects of theinvention. If aspects of the invention are described as “comprising” afeature, embodiments also are contemplated “consisting of or “consistingessentially of” the feature.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific embodiments, without undueexperimentation, without departing from the general concept of thepresent invention. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed embodiments, based on the teaching and guidance presentedherein. It is to be understood that the phraseology or terminologyherein is for the purpose of description and not of limitation, suchthat the terminology or phraseology of the present specification is tobe interpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present invention should not be limited byany of the above-described exemplary embodiments, but should be definedonly in accordance with the following claims and their equivalents.

All of the various aspects, embodiments, and options described hereincan be combined in any and all variations.

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent that any meaning or definition of a term in this documentconflicts with any meaning or definition of the same term in a documentincorporated by reference, the meaning or definition assigned to thatterm in this document shall govern.

1-65. (canceled)
 66. A method of treating Parkinson's disease,comprising administering to a subject in need thereof a pharmaceuticalcomposition comprising a pamoate salt of a monoamine anti-Parkinson'sdisease agent and a pharmaceutically acceptable carrier.
 67. The methodof claim 66, wherein the pharmaceutically acceptable carrier is aviscous aqueous or nonaqueous carrier.
 68. The method of claim 66,wherein the pharmaceutical composition is administered by injection. 69.The method of claim 67, wherein administering the pharmaceuticalcomposition provides a duration of efficacy of the monoamine for leastabout 7 days.
 70. The method of claim 66, wherein the pharmaceuticalcomposition comprises a crystalline Form I of pamoate salt ofrotigotine, which is characterized by an X-ray Powder diffraction(“XRPD”) spectrum having both peaks at 4.6 and 9.3, ±0.2° 2-theta. 71.The method of claim 66, wherein the pharmaceutical composition comprisesa crystalline form of pamoate salt of ropinirole, wherein thecrystalline form is Form A, Form B, Form C, Form D, or Form E, whereinForm A is characterized by an XRPD spectrum having the following peaks:4.3, 17.1, 18.6, and 20.5, ±0.2° 2-theta; Form B is characterized by anXRPD spectrum having the following peaks: 11.5, 16.4, 21.0, 23.1, 23.4,and 26.2, ±0.2° 2-theta; Form C is characterized by an XRPD spectrumhaving peaks at 16.1 and 18.8, ±0.2° 2-theta; Form D is characterized byan XRPD spectrum having the following peaks: 14.3, 17.9, and 25.2, ±0.2°2-theta; and Form E is characterized by an XRPD spectrum having thefollowing peaks: 11.7, 12.0, and 21.0, ±0.2° 2-theta.
 72. The method ofclaim 66, wherein the pharmaceutical composition comprises a crystallineform of pamoate salt of pramipexole, wherein the crystalline form isForm 1, Form 2, Form 3, or Form 4, wherein Form 1 is characterized by anXRPD spectrum having one or more of the following peaks: 13.8, 15.3, and21.1, ±0.2° 2-theta; Form 2 is characterized by an XRPD spectrum havingone or more of the following peaks: 12.0, 15.0, 20.4, and 20.9, ±0.2°2-theta; Form 3 is characterized by an XRPD spectrum having one or moreof the following peaks: 10.7, 12.7, 13.5, and 14.9, ±0.2° 2-theta; andForm 4 is characterized by an XRPD spectrum having the following peaks:6.1, and 17.9, ±0.2° 2-theta.
 73. The method of claim 72, wherein thecrystalline form is Form 1, wherein the Form 1 is characterized by anXRPD spectrum having the following peaks: 7.7, 11.8, 13.8, 15.3, 18.9,21.1, 23.1, 23.7, and 26.4, ±0.2° 2-theta.
 74. The method of claim 72,wherein the crystalline form is Form 2, wherein the Form 2 ischaracterized by an XRPD spectrum having the following peaks: 12.0,15.0, 20.4, 20.9, 22.5, and 23.3, ±0.2° 2-theta.
 75. The method of claim72, wherein the crystalline form is Form 3, wherein the Form 3 ischaracterized by an XRPD spectrum having the following peaks: 10.7,12.7, 13.5, 14.9, 18.7, and 22.3, ±0.2° 2-theta.
 76. The method of claim72, wherein the crystalline form is Form 4, wherein the Form 4 ischaracterized by (a) an XRPD spectrum having the following peaks: 6.1,17.9, 21.3, and 23.2, ±0.2° 2-theta.